Clock Regulation of Metabolites Reveals Coupling between Transcription and Metabolism
The intricate connection between the circadian clock and metabolism remains poorly understood. We used high temporal resolution metabolite profiling to explore clock regulation of mouse liver and cell autonomous metabolism. In liver, ~50% of metabolites were circadian, with enrichment of nucleotide, amino acid, and methylation pathways. In U2 OS cells, 28% were circadian, including amino acids and NAD biosynthesis metabolites. Eighteen metabolites oscillated in both systems and a subset of
... in primary hepatocytes. These 18 metabolites were enriched in methylation and amino acid pathways. To assess clock-dependence of these rhythms, we used genetic perturbation. BMAL1 knockdown diminished metabolite rhythms, while CRY1 or CRY2 perturbation generally shortened/lengthened rhythms, respectively. Surprisingly, CRY1 knockdown induced 8 h rhythms in amino acid, methylation, and vitamin metabolites, decoupling metabolite from transcriptional rhythms, with potential impact on nutrient sensing in vivo. These results provide the first comprehensive views of circadian liver and cell autonomous metabolism. Blurb Using high temporal resolution metabolite profiling, XXX et al show that over 50% of liver metabolites are circadian, with a significant overlap of cycling metabolites between mouse and human liver, especially those involved in epigenetic regulation. Coupling of metabolite with transcriptional rhythms is regulated by core clock genes. Krishnaiah et al. and 32 h rhythmic metabolites, decoupling the transcriptional and metabolic oscillations. Collectively, these results have important implications for experimental design as well as circadian regulation of metabolism in vitro and in vivo. Krishnaiah et al.